Advancements in genetic circuits as part of intelligent biotherapy for the treatment of bladder cancer: A review

Abstract

Background: Bladder cancer poses a significant threat to human health. In recent years, genetic circuit therapy has emerged as a novel alternative for precision tumor treatment, demonstrating promising potential for clinical application. Compared to traditional drugs, genetic circuits - typically carried by plasmids - offer advantages such as modularity, druggability, and shorter drug development cycles. These circuits can identify multiple molecular signals from tumors and integrate them through logic gates to specifically target tumor cells. Furthermore, by assembling effector modules, they can induce specific forms of cell death in tumor cells or alter malignant phenotypes, thereby reshaping the immune microenvironment to produce efficient, durable, and controllable antitumor effects. The urinary system serves as an ideal model for this new therapy due to its accessibility from the outside. Several genetic circuits have already been validated for the treatment of bladder cancer. This review outlined the effectiveness and potential value of genetic circuits in bladder cancer therapy.

Objective: This review focused on the design principles of genetic circuits, their ability to recognize and convert signals, their therapeutic signal output, and the associated delivery vehicles. We also discussed the challenges and future prospects of genetic circuits as a novel form of "intelligent biotherapy."

Conclusion: The gene circuit can identify multiple signals, processing complex information, and generating multiple effects, thus providing a new approach for personalized treatment of tumors.

Keywords: Biotherapy; Bladder cancer; Genetic circuits; Precise therapy.

Figure 1

Milestones in the development of synthetic biology in tumor therapy Abbreviations: ADAR: Adenosine deaminases acting on ribonucleic acids; CAR-T: Chimeric antigen receptor T-cells; Cas: CRISPR-associated protein; CRISPR: Clustered regularly interspaced short palindromic repeats.

Figure 2

Basic principles of genetic circuit design Abbreviations: CRISPRa: CRISPR activation; CRISPRi: CRISPR inactivation; ETS-1: V-ets avian erythroblastosis virus E26 oncogene homolog 1; Get1: Grainyhead-like epithelial transactivator 1; mRNA: Messenger RNA; miRNA: MicroRNA; NAND: NOT-AN; ncRNA: Non-coding RNA; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; Poly(A): Poly-adenine tail; P53: Tumor protein P53; RNA: Ribonucleic acid; rtTA: Reverse tetracycline transactivator; tet: Tetracycline; tTA: Tetracycline transactivator.